This invention relates to a prosthesis for implantation into a mammal comprising bioabsorbable substances insolubilized by physical methods, instead of chemical-reagent cross-linking, that can be used in place of conventional prostheses coated with bioabsorbable substances and to cytokines insolubilized on the bioabable substances. The invention also relates to a method of manufacturing such prostheses.
1. Field of the Invention
This invention concerns a prosthesis comprising bioabsorbable substances that can prevent blood leakage, has non-thrombogenic property and host cell afnnity, and is free from side effects caused by chemical reagents typically used during the manufactuting process of conventional prostheses. The prosthesis can include growth factor, such as fibroblast growth factor, for stimulating growth of cells into and around the prostheses, such as fibroblasts and/or endothelial cells.
2. Description of the Prior Art
Important and necessary characteristics for a prosthesis are nondegradation strength in vivo, adequate mechanical properties such as morphology retention, softness and flexibility, nonblood leakage and the followings:
(1) Excellent nonthrombogenic effect, PA1 (2) Biological acceptability, such as nontoxicity, noncarcinogenicity, nonimmunogenicity and nonforeign body reaction, and PA1 (3) Excellent healing ability of neointima. PA1 1. A prosthesis comprising a porous substrate and one or more bioabsorbable substances that are insolubilized by at least one physical method such as entanglement, dry-up, thermal cross-linking, gamma irradiation, ultraviolet irradiation, and swelling up by hyper hydration with electric charge. These physical methods do not require chemical reagents which are used for conventional coated prostheses. The prosthesis of the invention can include growth factors, such as fibroblast growth factor, for increasing the rate of acceptance by the host of the implanted prothesis. The invented prosthesis can provide a high affinity for host cells and is free from the side effects caused by chemical reagents. PA1 2. The prosthesis retaining one or more bioabsorbable substance by physical means rather than chemical means of this invention can be prepared by way of repeated inflitration of a porous prosthesis with a dispersed solution of a bioabsorbable substance having low viscosity, such as a viscosity at 22.degree. C. of less than or equal to 1000 mpa's measured with viscometer. When collagen fiber is used as the bioabsorbable substance, the dispersed solution can be a fiber collagen suspension, where the concentration of the collagen is equal to or less than about 1.0 wt. %. Ihe prosthesis can be placed in the collagen fiber solution and/or the collagen fiber solution can be placed inside the prosthesis substrate, and the collagen fibers can be captured within the prosthesis substrate wall, such as within the pores of the prosthesis substrate wall, by providing a pressure differential between inside and outside of the prosthesis. The captured bioabsorbable substance(s) (i.e., collagen fibers) are insolubilized by a physical method, such as entanglement, dry-up, thermal cross-linking, gamma irradiation, ultraviolet irradiation and swelling up by hyper hydration with electric charge. Thereafter, growth factors, such as fibroblast growth factor, can be bound to the bioabsorbable substance(s). PA1 3. A prosthesis made of bioabsorbable substance(s) where the bioabsorbable substance(s) is shaped by itself into a prosthesis without the need for the supporting structure of a porous substrate, and then immobilizing or insolubilizing the bioabsorbable materials in place by the physical method of this invention, such as by dry-up, thermal cross-linking, gamma irradiation, ultraviolet irradiation, and/or swelling up by hyper hydration with electric charge. After the immobilizing or insolubilizing of the bioabsorbable substance(s), growth factors, such as fibroblast growth factor, can be bound thereto. PA1 (1) The tissues and cells are large enough to be easily interstices of the porous substrates, as well as with each other. PA1 (2) The tissues and cells can give suitable environment for host cell migration and proliferation even if they die during sterilization or drying up. If the tissues can maintain their living ability, they will act as promoters of neointima formation on the prosthesis surface. PA1 (3) Autologous tissues and cells can synthesize some cytokines such as cell growth factors. With these cytokines, tissues and cells can maintain their living ability and stimulate each other to survive and to create organs where they are located.
Most cardiovascular wall prostheses are made of woven, knitted or braided polyester fibers or expanded polytetrafluoroethylene. To obtain good neointima formation, a porous substrate has been adopted for the prostheses.
To prevent blood leakage through the porous prostheses, they are uually sealed with fresh blood before implantation. This procedure is called "preclotting." Recently, conventional cardiovascular wall prostheses are coated with bioabsorbable substances such as collagen, albumin or gelatin during their manufacturing process instead of predotting during surgery.
These bioabsorbable substances are insolubilized by cross-linking with a chemical reagent such as glutaraldehyde, formaldehyde or diisocyanate. They are, however, cytotoxic, and even after a long period of time, adverse side effects result in causing foreign body reaction against the host tissues. According to recent scientific papers, it is recognized that the healing is always delayed due to noninfectious inflammation, fluid retention around the prosthesis, and/or unusually continuous fever after implantation.
When conventional vascular prostheses are used, porous ones may be selected to yield tissue ingrowth from the adventitia side to the luminal side. Usually, these pores are sealed with a fibrin network produced by fresh blood (preclotting). However, the fibrin network produced by preclotting always has some risk of being dissolved because of fibrinolysis phenomenons. This is especially true when a large amount of anticoagulants is used during and after implantation, and bleeding due to fibrinolysis can result in serious patient conditions. To prevent such undesired bleeding, recent porous vascular prostheses are coated with bioabsorbable substances cross-linked with glutaraldehyde, formaldehyde or diisocyanate. In the present invention, alternative means or methods for such chemical cross-linking is used, as described below.
As to conventional coated prostheses, collagen, gelatin and albumin can be used as bioabsorbable substances. These bioabsorbable substances originally have high affinity to host cells unless they are chemically treated. They can induce an excellent neointima fonration without side effects before chemical treatment, however, their advantages are not employed satisfactorily. From the stand point of safety against bleeding during surgery, conventional coated prostheses have been used in humans despite of their adverse side effects, since recent surgeries require a large amount of anticoagulants during and after implantation. As a natural consequence, undesirable results after conventional prosthesis implantation have been reported in cases of old and/or weak patients, generally patients with poor or high risk conditions. When emphasis is placed on prevention of blood leakage, prevention of the side effects by the coated substances is difficult. This dilemma has been impossible to solve as long as the conventional coated prostheses have been used.
As for the manufacturing process, a highly viscous suspension of the bioabsorbable substances has been used in order to coat and impregnate the conventional prostheses. However, these substances only accumulate on the luminal surface due to their high viscosity, which tends to result in insufficient impregnation inside the prosthesis wall and easy detachment of impregnant from the surface of the prosthesis.